Dutta, S., Pang, M., Donahue, R.R, Chou, T.F., Seifert, A.W., and Gradinaru, V. (2025). Parkinson’s disease modeling in regenerative spiny mice (Acomys dimidiatus) captures key disease-relevant behavioral, histological, and molecular signatures bioRxiv. doi: 10.1101/2025.11.06.687049
License: This is an open access collection distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
We use this collection and it's working
Created: August 12, 2025
Last Modified: June 01, 2026
Collection Integer ID: 224513
Keywords: disease modeling in regenerative spiny mice, regenerative spiny mice, mechanisms of neurodegeneration, synuclein, parkinson, hallmarks of pd pathology, extensive proteomic alterations in dopaminergic neuron, multifactorial neurodegenerative disorder, key pathological hallmark of pd, neurodegeneration, mice, positive αsyn inclusions across multiple brain region, nigrostriatal pathway, mouse αsyn pff, robust regeneration of multiple tissue, proteasomal pathway, greater nigrostriatal degeneration, dopaminergic neuron, spiny mouse, relevant pathophysiology across species, regenerative intervention strategies in pd, pd pathology, key pathological hallmark, cell spatial proteomic, pathway, robust regeneration, rodent, neuron, spatial proteomic
Funders Acknowledgements:
Aligning Science Across Parkinson’s (ASAP)/ Michael J. Fox Foundation for Parkinson’s Research (MJFF),
Grant ID: ASAP-020495
Abstract
Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder that has been modeled extensively in
animals, primarily rodents, but also in non-human primates and non-mammalian organisms. However, no single animal model fully recapitulates the hallmarks of PD pathology. Here, we extend this work by modeling PD for the first time in the spiny mouse (Acomys dimidiatus), a mammal notable for its robust regeneration of multiple tissues. We show that the nigrostriatal pathway of A. dimidiatus is vulnerable to both chronic α-synuclein (αSyn) preformed fibril-induced aggregation and acute 6-hydroxydopamine (6-OHDA) toxicity. Mouse αSyn PFFs produced widespread pS129-positive αSyn inclusions across multiple brain regions, mirroring a key pathological hallmark of PD. Compared to C57BL/6J mice, A. dimidiatus exhibited more pronounced behavioral impairments, greater nigrostriatal degeneration, and a higher pS129-αSyn inclusion burden within substantia nigra pars compacta (SNpc) neurons. To probe the molecular underpinnings behind the vulnerability, we performed single-cell spatial proteomics, which revealed extensive proteomic alterations in dopaminergic neurons associated with αSyn aggregation. While proteasomal pathways emerged as major PD-related hubs conserved in both species, multiple proteins and pathways were uniquely differentially dysregulated between the two species. Notably, proteomic analysis identified heightened astrocytic activation in the SNpc, which we validated histologically, suggesting a distinct glial response compared to mice. Together, these findings expand our understanding of PD-relevant pathophysiology across species and establish A. dimidiatus as a model for studying mechanisms of neurodegeneration and regenerative intervention strategies in PD. PNAS may not allow for final submission (similar ones highlighted in the later sections)
